ADP indicates adenosine diphosphate; AGAT, L -arginine:glycine amidinotransferase; ATP, adenosine triphosphate; CK, creatinine kinase; GAA, guanidinoacetate; GAMT, guanidinoacetate N-methyltransferase; MS, methionine synthase; MTHF, methyltetrahydrofolate; SAH, S -adenosylhomocysteine; SAM, S -adenosylmethionine; and THF, tetrahydrofolate.

Pascual JM , Roe CR. Systemic Metabolic Abnormalities in Adult-onset Acid Maltase Deficiency : Beyond Muscle Glycogen Accumulation. JAMA Neurol. Author Affiliations: Rare Brain Disorders Clinic and Laboratory, Departments of Neurology and Neurotherapeutics Drs Pascual and Roe , Physiology and Pediatrics Dr Pascual , The University of Texas Southwestern Medical Center, Dallas.

Importance The physiological relevance of acid maltase acid α-glucosidase, an enzyme that degrades lysosomal glycogen is well recognized in liver and muscle. In late adult —onset acid maltase deficiency glycogen storage disease type II [GSD II] , glycogen accumulates inside muscular lysosomes in the context of reduced enzymatic activity present not only in muscle, but also throughout the organism.

Yet, disease manifestations are commonly attributed to lysosomal disruption and autophagic vesicle buildup inside the myofiber due to a lack of obvious hepatic or broader metabolic dysfunction.

However, current therapies primarily focused on reducing glycogen deposition by dietary or enzyme replacement have not been consistently beneficial, providing the motivation for a better understanding of disease mechanisms.

Results Patients exhibited evidence for disturbed energy metabolism contributing to a chronic catabolic state and those who were studied further also displayed diminished plasma methylation capacity and elevated levels of insulin-like growth factor type 1 and its carrier protein insulin-like growth factor binding protein 3 IGFBP Conclusions and Relevance The simplest unifying interpretation of these abnormalities is nutrient sensor disturbance with secondary energy failure leading to a chronic catabolic state.

Data also provide the framework for the investigation of potentially beneficial interventions, including methylation supplementation, as adjuncts specifically targeted to ameliorate the systemic metabolic abnormalities of this disorder.

Glycogen metabolism occurs throughout the organism, particularly in organs that expend energy generating work and maintaining metabolic homeostasis, such as muscle and liver. Instead, striated skeletal and sphincter muscles especially the diaphragm are severely affected, causing dysphagia, sphincter hypotonia, progressive limb weakness, muscular atrophy, and ultimately, respiratory failure.

Elevations of serum enzymes creatine kinase [CK] and transaminases and, occasionally, decreases in plasma alanine and glutamine levels, have generally been attributed to the myopathy, 6 , 7 such that there has been no systematic focus on the potential contribution of additional organ derangement to the disorder.

The current diet includes reduced carbohydrate and increased protein intake, often with alanine supplementation and programmed physical exercise. From a more critical perspective, they may also be taken to suggest the existence of additional, unrecognized, and uncorrected metabolic derangements other than compromised glycogen degradation that may contribute to the pathogenesis of this disorder and, perhaps, to an inadequate response to current therapies.

In this study, we set out to provide a systematic overview of metabolism and methylation capacity using widely available analytical methods by evaluating secondary compromise of 1 the citric acid cycle CAC , 2 methylation capacity, and 3 nutrient sensor interaction in as many as 33 patients ie, not all patients were available for all assessments treated only with diet.

We reasoned that, if affected, these factors may reflect an underlying energy-deficient state contributing to the progressive clinical deterioration of these patients.

Standard informed consent and ethical procedures were followed. One patient received triheptanoin supplementation solely for analytical purposes rather than to test clinical efficacy under an instutional review board—approved protocol and Food and Drug Administration IND Lysosomal α-glucosidase deficiency was confirmed in all patients by leukocyte enzymatic assay prompted by myopathic clinical features.

All available patients known to us with disease onset after age 15 years were included. They were sequentially enrolled during 1 year on the basis of clinical and enzymatic criteria. Not all patients were available for participation in all analytical studies, and additional selection criteria were not imposed on those who were able to participate in further study.

Disease onset was defined as the time when weakness or fatigability first led to general medical attention. Additional data included demographic profiles, ambulatory and ventilatory assistance, nutritional route, and Walton and Gardner-Medwin 14 and Slonim 10 functional scores.

All blood assays were performed on plasma obtained from overnight fasting samples. Methods for quantitative acylcarnitines, plasma amino acids, and urinary organic acids, and their reference ranges have been described previously. Samples for urine organic acid analyses were available in a subset of 19 patients.

Blood chemistry analyses included the following levels: glucose, serum urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, and CK.

Total plasma homocysteine was measured by high-performance liquid chromatography with fluorescence detection. Plasma IGF-1, insulin-like growth factor binding protein-3 IGFBP-3 , and growth hormone GH were measured in all patients by D. Laboratories, Houston, Texas.

The results were compared to age-related standards because both IGF-1 and IGFBP-3 decrease with age. Statistical results were obtained with GraphPad Prism version 4. Patient age ranged from 15 to 72 years and included 15 females and 18 males whose symptom duration ranged from 2 to 48 years Table 1.

As noted, not all patients were available for participation in all analytical studies, and the tables allow for correlative patient identification. Of the 33, at the time of blood and urine testing, 10 required a wheelchair, 18 were ambulatory, and 5 were ambulatory but required assistive devices.

Frozen samples for metabolic analysis propionylcarnitine, alanine, and glutamine were obtained from all 33 patients.

Urinary citrate was measured in 26 patients. Although follow-up analyses were beyond the scope of this study, 4 patients were tested again after 7 months, to evaluate whether urinary citrate excretion was subject to fluctuation.

Quantitative results for blood propionylcarnitine, alanine, glutamine, and urinary excretion of citrate are summarized in Table 2 together with patient ages.

No significant or consistent abnormalities were noted in the plasma amino acid or urinary organic acid analyses. Quantitative blood spot free carnitine and acylcarnitines acetyl-[C2] to linoleoyl-carnitine C were measured for all patients.

Propionylcarnitine was markedly reduced in most patients. Using our isotope dilution method, levels less than 1. All other acylcarnitine levels were consistently normal data not shown. Plasma amino acid analysis revealed that only 3 patients exhibited reduced levels of alanine or glutamine.

Urine samples for organic acid analysis were available from 26 patients. Only citrate levels demonstrated abnormalities. Four of 8 patients were studied again 7 months later.

However, 7 months later, their urine citrate levels had become elevated Figure 1 B , indicating that citrate excretion was subject to considerable fluctuation. No other organic acid abnormalities were noted to suggest metabolic derangement in fat oxidation, amino acid degradation, or vitamin deficiencies.

Plasma levels of IGF-1, IGFBP-3, and GH were measured in 26 patients who were available for further analytical testing Figure 2. Plasma levels of IGF-1 and IGFBP-3 gradually decrease with age. Therefore, patient results were compared with 3 healthy age groups years, years, and years.

In comparison with the corresponding reference ranges for age, all 26 patients exhibited significant elevations in both IGF-1 and IGFBP The previous data led to the hypothesis that, if IGF-1 and IGFBP-3 levels were elevated as the result of energy deficiency in GSD II, stimulation of anaplerosis ie, replenishment of CAC intermediates might reduce both plasma IGF-1 and IGFBP-3 levels and reduce urinary citrate excretion.

To test this hypothesis, the effects of a single oral triheptanoin meal an anaplerotic triglyceride 21 - 23 were tested in 1 patient. This year-old man was given a single dose of triheptanoin 0.

Plasma IGF-1, IGFBP-3, GH, and urinary citrate were measured over 6 hours following the meal. Growth hormone levels remained normal at less than 0. The integrity of methylation was assessed in a subset of 7 patients Table 3.

Homocysteine levels were normal. All 7 patients had plasma levels of creatinine, methionine, guanidinoacetate, and creatine additionally determined. Plasma methionine levels were variable ranging from 12 to 47 mM reference range, mM.

Guanidinoacetate levels were normal in all patients. However, all plasma creatinine levels were reduced below normal values, while plasma creatine levels were markedly elevated in all 7 patients. These elevations in creatine levels are too marked to be simply the consequence of increased protein dietary intake.

Other than simply muscle glycogen deposition and vesicular myofiber disruption, lines of evidence for a more extensive and complex metabolic dysfunction in GSD II may have, in retrospect, been present previously and are expanded in this study.

Together, these findings suggest an underlying energy deficiency producing a chronic catabolic state with the potential to significantly impact skeletal muscle function and preservation.

These lines of evidence are discussed sequentially. In GSD II, striated muscle wasting compromises physical performance and leads, ultimately, to respiratory failure. Unlike the infantile form, the late-onset disease does not usually affect the liver or heart.

Potential hepatic abnormalities in GSD II have been limited to mild increases in serum transaminase levels that, in fact, may be due to myopathy. Other liver dysfunction indicators, such as hypoglycemia and hyperammonemia, are not features of GSD II.

Unfortunately, ERT has not been consistently beneficial in all patients with GSD II. Residual enzyme activity in postmortem studies is significantly reduced in all organs tested. Nevertheless, these observations also support the need to develop additional treatment strategies focused on amelioration of secondary but closely interrelated biochemical abnormalities.

Plasma creatinine levels were below the reference range in all 7 patients studied. No other evidence was noted for disturbed propionate metabolism. Reduced blood levels of propionylcarnitine can reflect overconsumption of propionyl-coenzyme A CoA to augment succinyl-CoA in the CAC in an energy-deficiency state.

This decrease to less than 1. Urinary citrate was the only CAC intermediate that was increased in 8 of 19 patients Table 2. However, 4 of 19 patients had additional levels assayed 7 months later revealing that urinary citrate levels can significantly vary over time and are not a persistent abnormality for individual patients.

Three of these 4 patients exhibited normal citrate levels when first analyzed, which increased significantly 7 months later, possibly reflecting changes in their metabolic state or disease progression Figure 1 B. When mitochondrial citrate enters the cytosol, it must first be converted by adenosine triphosphate ATP —citrate lyase lyase to acetyl-CoA and oxaloacetate.

Acetyl-CoA produced by the lyase reaction can be converted by either acetyl-CoA carboxylase II ACC II to produce malonyl-CoA inhibiting β-oxidation or be used by acetyl-CoA carboxylase I ACC I to facilitate fatty acid synthesis. Of note, and related, adenosine monophosphate AMP —activated protein kinase AMPK activation by reduced ATP stimulates cytosolic catabolic pathways that normally enhance ATP synthesis while inhibiting biosynthetic reactions that consume ATP.

The result is a catabolic state. Active AMPK inhibits both ACC I and ACC II, and may contribute to the intermittent excessive urinary excretion of cytosolic citrate observed in patients with GSD II.

As observed in the adult form of GSD IV adult polyglucosan body disease , 22 there is also evidence for a secondary impairment of the integrated pathways of methylation in GSD II Table 3. These abnormalities included a reduced SAM level, increased SAH level, elevated creatine level, and reduced creatinine level.

These integrated pathways require ATP as depicted in Figure 4. The increased plasma levels of creatine associated with decreased levels of creatinine suggest compromised synthesis and availability of creatine phosphate that also requires ATP.

This observation further supports the existence of a potential compromise of intracellular energy metabolism.

Similar abnormalities were observed in patients with GSD IV in whom, additionally and except for creatinine levels , normalization was observed following 6 months of the anaplerotic triheptanoin diet.

In late-onset GSD II lysosomal acid α-glucosidase is the only defective enzyme involved in glycogen degradation. Although designated as a glucosidase, the enzyme also displays acid-debrancher activity. However, because the cytoplasmic glycogenolytic enzymes active at neutral pH are unaffected in GSD II, the progressive glycogen deposition in the cytosol as well as in lysosomes remains unexplained.

The cytosolic glycogen accumulation might result from continued glycogen synthesis due to ineffective regulation of glycogen synthase by several ATP-dependent protein kinases, including AMPK. This possibility has also been suggested for late-onset GSD IV 22 and McArdle disease GSD type V.

Healthy individuals receiving high-protein diets exhibit modest increases in IGF-1 levels. For them, each 1-SD increment in total protein, dairy protein, and calcium intake is associated with an increase in plasma IGF-1 levels of only approximately 2. However, IGFBP-3 levels are unaffected.

Therefore, the significantly elevated plasma levels of both IGF-1 and IGFBP-3 in patients with GSD II in the context of normal growth hormone levels are not due to high-protein intake.

These extreme plasma levels of IGF-1 in GSD II may also reflect a disturbance in nutrient sensor interactions based on energy deficiency in muscle metabolism. Normally, intracellular IGF-1 inhibits the catabolic effects of active AMPK via serine-threonine kinase and permits activation of the mammalian target of rapamycin.

This stimulates biosynthetic reactions, cell proliferation, DNA synthesis, uptake of amino acids and glucose, and suppression of proteolysis. The significant effects in a year-old woman of protein sparing, decreased proteolysis, and reversal of acute respiratory failure coupled with a return to a normal life style have been previously described by us.

In the current study, a year-old man received a single dose of triheptanoin 0. His plasma IGF-1 and IGFBP-3 levels decreased to normal levels. During the same period, his urinary citrate excretion also decreased Figure 3.

These effects may reflect the consequence of enhanced anaplerosis on the IGF-1 receptor and normalization of citrate metabolism, which are both dependent on enhanced ATP availability. In the context of all the results described earlier, this single observation and the related article 38 provide justification for further, systematic evaluation of anaplerotic therapy in this disorder.

In conclusion, these observations in patients with adult-onset GSD II suggest that there is a significant energy deficit in this disease that is reflected in metabolic abnormalities including reduced methylation capacity.

Thus, as also suspected by others, the pathogenetic mechanisms of GSD II seem to be broader than they were generally thought to be. These observations, together with our prior findings involving triheptanoin effects in GSD II and late-onset GSD IV 22 , 38 suggest that anaplerotic diet therapy and methylation supplements may assist in the future management of patients with GSD II.

Correspondence: Juan M. Pascual, MD, PhD, Rare Brain Disorders Clinic and Laboratory, The University of Texas Southwestern Medical Center, Harry Hines Blvd, Mail Code , Dallas, TX Author Contributions: Acquisition of data : Roe.

Analysis and interpretation of data : All authors. Drafting of the manuscript : All authors. Critical revision of the manuscript for important intellectual content : All authors.

Statistical analysis : Roe. Administrative, technical, and material support : Roe. Study supervision : Roe. Additional Contributions: Arnold Reuser, PhD, and Ans van der Ploeg, MD, PhD, Department of Clinical Genetics, Erasmus Universiteit, Rotterdam, the Netherlands, provided untreated samples from 26 patients for this study.

Teodoro Bottiglieri, PhD, Institute of Metabolic Disease, determined SAM, SAH, methionine, homocysteine, IGF-1, IGFBP-3, and GH plasma levels.

Cornelis Jakobs, PhD, Clinical Chemistry Department of the Free University of Amsterdam, Amsterdam, the Netherlands, analyzed the guanidinoacetate and creatine levels. Additional Information: Part of this study was performed at the Institute of Metabolic Disease, Baylor University Medical Center, Dallas.

full text icon Full Text. Download PDF Top of Article Abstract Methods Results Discussion Article Information References. View Large Download. Table 1. Demographic and Clinical Characteristics of Patients With GSD II. Table 2. Plasma and Urinary Metabolic Parameters in 33 Adult-onset Patients With GSD II.

Table 3. Plasma Indicators of Methylation Capacity in a Set of Adult-onset Patients With GSD II. Brown AM, Ransom BR. Astrocyte glycogen and brain energy metabolism. Roach PJ, Depaoli-Roach AA, Hurley TD, Tagliabracci VS. Glycogen and its metabolism: some new developments and old themes.

Biochem J. Hirschhorn R, Reuser AJJ. Glycogen storage disease type II: acid α-glucosidase acid maltase deficiency. In: Scriver CRBA, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease.

GSD types VI and IX can have very mild symptoms and may be underdiagnosed or not diagnosed until adulthood. Currently, there is no cure for GSD.

Treatment will vary depending on what type of GSD your child has; however, the overall goal is to maintain the proper level of glucose in the blood so cells have the fuel they need to prevent long-term complications. Until the early s, children with GSDs had few treatment options and none were very helpful.

Then it was discovered that ingesting uncooked cornstarch regularly throughout the day helped these children maintain a steady, safe glucose level. Cornstarch is a complex carbohydrate that is difficult for the body to digest; therefore it acts as a slow release carbohydrate and maintains normal blood glucose levels for a longer period of time than most carbohydrates in food.

Cornstarch therapy is combined with frequent meals eating every two to four hours of a diet that restricts sucrose table sugar , fructose sugar found in fruits and lactose only for those with GSD I. Typically, this means no fruit, juice, milk or sweets cookies, cakes, candy, ice cream, etc.

because these sugars end up as glycogen trapped in the liver. Infants need to be fed every two hours. Those who are not breastfed must take lactose-free formula.

Some types of GSD require a high-protein diet. Calcium, vitamin D and iron supplements maybe recommended to avoid deficits. Children need their blood glucose tested frequently throughout the day to make sure they are not hypoglycemic, which can be dangerous.

Some children, especially infants, may require overnight feeds to maintain safe blood glucose levels. For these children, a gastrostomy tube, often called a g-tube, is placed in the stomach to make overnight feedings via a continuous pump easier. The outlook depends on the type of GSD and the organs affected.

With recent advancements in therapy, treatment is effective in managing the types of glycogen storage disease that affect the liver.

Children may have an enlarged liver, but as they grow and the liver has more room, their prominent abdomen will be less noticeable. Other complications include benign noncancerous tumors in the liver, scarring cirrhosis of the liver and, if lipid levels remain high, the formation of fatty skin growths called xanthomas.

To manage complications, children with GSD should been seen by a doctor who understands GSDs every three to six months.

Blood work is needed every six months. Once a year, they need a kidney and liver ultrasound. Research into enzyme replacement therapy and gene therapy is promising and may improve the outlook for the future.

CHOP will be a site for upcoming gene therapy clinical trials for types I and III. The GSD Clinic will have more information. Glycogen Storage Disease GSD. Contact Us Online. Glycogen storage disorders occur in about one in 20, to 25, newborn babies. Manifestations of GSD often look like other health problems and may include: poor growth low blood glucose level hypoglycemia an enlarged liver may show as a bulging abdomen abnormal blood tests low muscle tone muscle pain and cramping during exercise too much acid in the blood acidosis fatigue A thorough medical history can also lead the doctor to suspect GSD since it is inherited.

Other diagnostic tests may include: blood tests to check blood glucose levels and how the liver, kidneys and muscles are functioning abdominal ultrasound to see if the liver is enlarged tissue biopsy to test a sample of tissue from muscle or liver to measure the level of glycogen or enzymes genetic testing, which can confirm a GSD.